Both Thyroid Hormone Receptor (TR)β1 and TRβ2 Isoforms Contribute to the Regulation of Hypothalamic Thyrotropin-Releasing Hormone

Thyroid hormones (TH) are essential regulators of vertebrate development and metabolism. Central mechanisms governing their production have evolved, with the β-TH receptor (TRβ) playing a key regulatory role in the negative feedback effects of circulating TH levels on production of hypothalamic TRH and hypophyseal TSH. Both TRβ-isoforms (TRβ1 and TRβ2) are expressed in the hypothalamus and pituitary. However, their respective roles in TH-dependent transcriptional regulation of TRH are undefined. We confirmed the preferential role of TRβ vs. TRα isoforms in TRH regulation in wild-type mice in vivo by using the TRβ preferential agonist GC-1. We next determined the effects of tissue-specific rescue of TRβ1 and TRβ2 isoforms by somatic gene transfer in hypothalami of TRβ null (TRβ−/−) mice. TH-dependent TRH transcriptional repression was impaired in TRβ−/− mice, but was restored by cotransfection of either TRβ1 or TRβ2 into the hypothalamus. TRβ1, but not TRβ2, displayed a role in ligand-independent activatio...